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1.
J Clin Invest ; 134(12)2024 Jun 17.
Article de Anglais | MEDLINE | ID: mdl-38950330

RÉSUMÉ

Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.


Sujet(s)
Résistance aux médicaments antinéoplasiques , Leucémie aigüe myéloïde , Nicotinamide , Tyrosine kinase-3 de type fms , Humains , Leucémie aigüe myéloïde/traitement médicamenteux , Leucémie aigüe myéloïde/génétique , Leucémie aigüe myéloïde/anatomopathologie , Leucémie aigüe myéloïde/métabolisme , Tyrosine kinase-3 de type fms/génétique , Tyrosine kinase-3 de type fms/antagonistes et inhibiteurs , Tyrosine kinase-3 de type fms/métabolisme , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Résistance aux médicaments antinéoplasiques/génétique , Animaux , Souris , Nicotinamide/analogues et dérivés , Nicotinamide/pharmacologie , Lignée cellulaire tumorale , Tests d'activité antitumorale sur modèle de xénogreffe , Femelle , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Mutation , Souris SCID , Souris de lignée NOD
2.
Cells ; 13(13)2024 Jun 24.
Article de Anglais | MEDLINE | ID: mdl-38994944

RÉSUMÉ

Current medical therapies for fibroids have major limitations due to their hypoestrogenic side effects. Based on our previous work showing the activation of NF-kB in fibroids, we hypothesized that inhibiting NF-kB in vivo would result in the shrinkage of tumors and reduced inflammation. Fibroid xenografts were implanted in SCID mice and treated daily with Bay 11-7082 (Bay) or vehicle for two months. Bay treatment led to a 50% reduction in tumor weight. RNAseq revealed decreased expression of genes related to cell proliferation, inflammation, extracellular matrix (ECM) composition, and growth factor expression. Validation through qRT-PCR, Western blotting, ELISA, and immunohistochemistry (IHC) confirmed these findings. Bay treatment reduced mRNA expression of cell cycle regulators (CCND1, E2F1, and CKS2), inflammatory markers (SPARC, TDO2, MYD88, TLR3, TLR6, IL6, TNFα, TNFRSF11A, and IL1ß), ECM remodelers (COL3A1, FN1, LOX, and TGFß3), growth factors (PRL, PDGFA, and VEGFC), progesterone receptor, and miR-29c and miR-200c. Collagen levels were reduced in Bay-treated xenografts. Western blotting and IHC showed decreased protein abundance in certain ECM components and inflammatory markers, but not cleaved caspase three. Ki67, CCND1, and E2F1 expression decreased with Bay treatment. This preclinical study suggests NF-kB inhibition as an effective fibroid treatment, suppressing genes involved in proliferation, inflammation, and ECM remodeling.


Sujet(s)
Prolifération cellulaire , Léiomyome , Nitriles , Sulfones , Animaux , Humains , Sulfones/pharmacologie , Sulfones/usage thérapeutique , Léiomyome/anatomopathologie , Léiomyome/traitement médicamenteux , Léiomyome/génétique , Léiomyome/métabolisme , Femelle , Souris , Nitriles/pharmacologie , Prolifération cellulaire/effets des médicaments et des substances chimiques , Souris SCID , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Facteur de transcription NF-kappa B/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffe , Lignée cellulaire tumorale , Tumeurs de l'utérus/anatomopathologie , Tumeurs de l'utérus/génétique , Tumeurs de l'utérus/traitement médicamenteux , Tumeurs de l'utérus/métabolisme
3.
Sheng Wu Gong Cheng Xue Bao ; 40(7): 2195-2210, 2024 Jul 25.
Article de Chinois | MEDLINE | ID: mdl-39044584

RÉSUMÉ

In recent years, virological, pathological, and immunological studies need to be carried out for the emerging anti-human immunodeficiency virus (HIV) therapies such as gene therapy, broadly neutralizing antibodies, and the derived chimeric antigen receptor (CAR)-T immunotherapy, which necessitates suitable, simple, and inexpensive small-animal models and methods for accurate quantification of the viral genome in the HIV-1 infected. In our research, the HIV-∆ENV-Jurkat-EGFP-mCherry cell line was engineered through the infection with a dual-labelled HIV pseudovirus. A nested quantitative PCR (nested-qPCR) method with the cellular genome as the integrated standard was established for the quantification of HIV proviral copies. We administered intravenous injections of healthy human peripheral blood mononuclear cell (PBMC) into NOD/Prkdcscid/IL2rgnull (NPG) mice. To verify engraftment kinetics, we analyzed the percentages of hCD45+, hCD3+, hCD4+, and hCD8+ cells in the peripheral blood of hu-PBMC-NPG mice. To evaluate HIV-1 infection in hu-PBMC-NPG mice, we inoculated these mice with HIV NL4-3-NanoLuc by intraperitoneal (IP) injection. We then monitored the luciferase expression by the small animal imaging system and measured the viral load in the spleen by qPCR. The infiltration of human PBMCs in mice was detected 3-5 weeks after intravenous injection, and the percentage of hCD45 in humanized mouse PBMCs were more than 25% five weeks after IP inoculation. The expression of the virus-associated luciferase protein was detected by luciferase imaging 27 days post infection. Moreover, the viral total DNA, RNA, and proviral DNA copies reached 18 000 copies/106 cells, 15 000 copies/µg RNA, and 15 000 copies/106 cells, respectively, in the mouse spleen. Taken together, we reported a convenient method for building a simple humanized mouse model of HuPBMC-NPG/severe combined immunodeficiency (SCID) by intravenous injection with hu-PBMCs without advanced surgical skills and irradiation. Furthermore, we established a convenient method for the efficient determination of proviral DNA to assess HIV replication in vivo, viral reservoir sizes, and efficacy of novel anti-HIV therapies including CAR-T immunotherapy and gene therapy.


Sujet(s)
ADN viral , Modèles animaux de maladie humaine , Infections à VIH , VIH-1 (Virus de l'Immunodéficience Humaine de type 1) , Provirus , Animaux , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/génétique , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Souris , Humains , Provirus/génétique , Infections à VIH/immunologie , Infections à VIH/virologie , ADN viral/génétique , Souris de lignée NOD , Souris SCID , Agranulocytes/immunologie , Charge virale
4.
BMC Cancer ; 24(1): 853, 2024 Jul 18.
Article de Anglais | MEDLINE | ID: mdl-39026155

RÉSUMÉ

BACKGROUND: Metformin, a widely prescribed antidiabetic drug, has shown several promising effects for cancer treatment. These effects have been shown to be mediated by dual modulation of the AMPK-mTORC1 axis, where AMPK acts upstream of mTORC1 to decrease its activity. Nevertheless, alternative pathways have been recently discovered suggesting that metformin can act through of different targets regulation. METHODS: We performed a transcriptome screening analysis using HeLa xenograft tumors generated in NOD-SCID mice treated with or without metformin to examine genes regulated by metformin. Western Blot analysis, Immunohistochemical staining, and RT-qPCR were used to confirm alterations in gene expression. The TNMplot and GEPIA2 platform were used for in silico analysis of genes found up-regulated by metformin, in cervical cancer patients. We performed an AMPK knock-down using AMPK-targeted siRNAs and mTOR inhibition with rapamycin to investigate the molecular mechanisms underlying the effect of metformin in cervical cancer cell lines. RESULTS: We shown that metformin decreases tumor growth and increased the expression of a group of antitumoral genes involved in DNA-binding transcription activator activity, hormonal response, and Dcp1-Dcp2 mRNA-decapping complex. We demonstrated that ZFP36 could act as a new molecular target increased by metformin. mTORC1 inhibition using rapamycin induces ZFP36 expression, which could suggest that metformin increases ZFP36 expression and requires mTORC1 inhibition for such effect. Surprisingly, in HeLa cells AMPK inhibition did not affect ZFP36 expression, suggesting that additional signal transducers related to suppressing mTORC1 activity, could be involved. CONCLUSIONS: These results highlight the importance of ZFP36 activation in response to metformin treatment involving mTORC1 inhibition.


Sujet(s)
Complexe-1 cible mécanistique de la rapamycine , Metformine , Tumeurs du col de l'utérus , Tests d'activité antitumorale sur modèle de xénogreffe , Humains , Metformine/pharmacologie , Complexe-1 cible mécanistique de la rapamycine/métabolisme , Complexe-1 cible mécanistique de la rapamycine/antagonistes et inhibiteurs , Tumeurs du col de l'utérus/traitement médicamenteux , Tumeurs du col de l'utérus/métabolisme , Tumeurs du col de l'utérus/anatomopathologie , Tumeurs du col de l'utérus/génétique , Femelle , Animaux , Souris , Cellules HeLa , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Souris SCID , Souris de lignée NOD , Prolifération cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Transduction du signal/effets des médicaments et des substances chimiques , Sirolimus/pharmacologie
5.
J Exp Clin Cancer Res ; 43(1): 202, 2024 Jul 22.
Article de Anglais | MEDLINE | ID: mdl-39034411

RÉSUMÉ

BACKGROUND: Lung cancer remains one of the most prevalent cancer types worldwide, with a high mortality rate. Upregulation of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) may represent a key mechanism for evading immune surveillance. Immune checkpoint blockade (ICB) antibodies against PD-1 or PD-L1 are therefore widely used to treat patients with lung cancer. However, the mechanisms by which lung cancer and neutrophils in the microenvironment sustain PD-L1 expression and impart stronger inhibition of CD8+ T cell function remain unclear. METHODS: We investigated the role and underlying mechanism by which PD-L1+ lung cancer and PD-L1+ neutrophils impede the function of CD8+ T cells through magnetic bead cell sorting, quantitative real-time polymerase chain reaction (RT-PCR), western blotting, enzyme-linked immunosorbent assays, confocal immunofluorescence, gene silencing, flow cytometry, etc. In vivo efficacy and safety studies were conducted using (Non-obeseDiabetes/severe combined immune deficiency) SCID/NOD mice. Additionally, we collected clinical and prognostic data from 208 patients who underwent curative lung cancer resection between 2017 and 2018. RESULTS: We demonstrated that C-X-C motif chemokine ligand 5 (CXCL5) is markedly overexpressed in lung cancer cells and is positively correlated with a poor prognosis in patients with lung cancer. Mechanistically, CXCL5 activates the phosphorylation of the Paxillin/AKT signaling cascade, leading to upregulation of PD-L1 expression and the formation of a positive feedback loop. Moreover, CXCL5 attracts neutrophils, compromising CD8+ T cell-dependent antitumor immunity. These PD-L1+ neutrophils aggravate CD8+ T cell exhaustion following lung cancer domestication. Combined treatment with anti-CXCL5 and anti-PD-L1 antibodies significantly inhibits tumor growth in vivo. CONCLUSIONS: Our findings collectively demonstrate that CXCL5 promotes immune escape through PD-L1 upregulation in lung cancer and neutrophils chemotaxis through autocrine and paracrine mechanisms. CXCL5 may serve as a potential therapeutic target in synergy with ICBs in lung cancer immunotherapy.


Sujet(s)
Antigène CD274 , Lymphocytes T CD8+ , Chimiokine CXCL5 , Tumeurs du poumon , Granulocytes neutrophiles , Protéines proto-oncogènes c-akt , Humains , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/métabolisme , Tumeurs du poumon/immunologie , Tumeurs du poumon/métabolisme , Tumeurs du poumon/anatomopathologie , Souris , Animaux , Granulocytes neutrophiles/métabolisme , Granulocytes neutrophiles/immunologie , Chimiokine CXCL5/métabolisme , Chimiokine CXCL5/génétique , Antigène CD274/métabolisme , Antigène CD274/génétique , Protéines proto-oncogènes c-akt/métabolisme , Phosphorylation , Transduction du signal , Régulation positive , Femelle , Mâle , Chimiotaxie , Souris de lignée NOD , Souris SCID
6.
J Immunother Cancer ; 12(7)2024 Jul 23.
Article de Anglais | MEDLINE | ID: mdl-39043602

RÉSUMÉ

BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable remission in patients with B-cell malignancies. However, its efficacy in treating solid tumors remains limited. Here, we investigated a combination therapy approach using an engineered long-acting interleukin (IL)-7 (rhIL-7-hyFc or NT-I7) and CAR-T cells targeting three antigens, glypican-2 (GPC2), glypican-3 (GPC3), and mesothelin (MSLN), against multiple solid tumor types including liver cancer, neuroblastoma, ovarian cancer, and pancreatic cancer in mice. METHODS: CAR-T cells targeting GPC2, GPC3, and MSLN were used in combination with NT-I7 to assess the anticancer activity. Xenograft tumor models, including the liver cancer orthotopic model, were established using NOD scid gamma mice engrafted with cell lines derived from hepatocellular carcinoma, neuroblastoma, ovarian cancer, and pancreatic cancer. The mice were monitored by bioluminescence in vivo tumor imaging and tumor volume measurement using a caliper. Immunophenotyping of CAR-T cells on NT-I7 stimulation was evaluated for memory markers, exhaust markers, and T-cell signaling molecules by flow cytometry and western blotting. RESULTS: Compared with the IL-2 combination, preclinical evaluation of NT-I7 exhibited regression of solid tumors via enhanced occupancy of CD4+ CAR-T, improved T-cell expansion, reduced exhaustion markers (programmed cell death protein 1 or PD-1 and lymphocyte-activation gene 3 or LAG-3) expression, and increased generation of stem cell-like memory CAR-T cells. The STAT5 pathway was demonstrated to be downstream of NT-I7 signaling, mediated by increased expression of the IL-7 receptor expression in CAR-T cells. Furthermore, CAR-T cells improved efficacy against tumors with low antigen density when combined with NT-I7 in mice, presenting an avenue for patients with heterogeneous antigenic profiles. CONCLUSION: This study provides a rationale for NT-I7 plus CAR-T cell combination therapy for solid tumors in humans.


Sujet(s)
Immunothérapie adoptive , Interleukine-7 , Animaux , Humains , Souris , Immunothérapie adoptive/méthodes , Femelle , Tumeurs/thérapie , Tumeurs/immunologie , Tests d'activité antitumorale sur modèle de xénogreffe , Lignée cellulaire tumorale , Récepteurs chimériques pour l'antigène/immunologie , Souris SCID , Souris de lignée NOD , Mésothéline
7.
Nat Commun ; 15(1): 6222, 2024 Jul 23.
Article de Anglais | MEDLINE | ID: mdl-39043633

RÉSUMÉ

Chimeric antigen receptor (CAR) T-cells targeting Fibroblast Growth Factor Receptor 4 (FGFR4), a highly expressed surface tyrosine receptor in rhabdomyosarcoma (RMS), are already in the clinical phase of development, but tumour heterogeneity and suboptimal activation might hamper their potency. Here we report an optimization strategy of the co-stimulatory and targeting properties of a FGFR4 CAR. We replace the CD8 hinge and transmembrane domain and the 4-1BB co-stimulatory domain with those of CD28. The resulting CARs display enhanced anti-tumor activity in several RMS xenograft models except for an aggressive tumour cell line, RMS559. By searching for a direct target of the RMS core-regulatory transcription factor MYOD1, we identify another surface protein, CD276, as a potential target. Bicistronic CARs (BiCisCAR) targeting both FGFR4 and CD276, containing two distinct co-stimulatory domains, have superior prolonged persistent and invigorated anti-tumor activities compared to the optimized FGFR4-specific CAR and the other BiCisCAR with the same 4-1BB co-stimulatory domain. Our study thus lays down the proof-of-principle for a CAR T-cell therapy targeting both FGFR4 and CD276 in RMS.


Sujet(s)
Antigènes B7 , Immunothérapie adoptive , Récepteur FGFR4 , Récepteurs chimériques pour l'antigène , Rhabdomyosarcome , Tests d'activité antitumorale sur modèle de xénogreffe , Récepteur FGFR4/métabolisme , Récepteur FGFR4/génétique , Rhabdomyosarcome/thérapie , Rhabdomyosarcome/immunologie , Rhabdomyosarcome/génétique , Humains , Animaux , Récepteurs chimériques pour l'antigène/immunologie , Récepteurs chimériques pour l'antigène/métabolisme , Lignée cellulaire tumorale , Souris , Immunothérapie adoptive/méthodes , Antigènes B7/métabolisme , Antigènes B7/immunologie , Antigènes B7/génétique , Protéine MyoD/métabolisme , Protéine MyoD/génétique , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Enfant , Femelle , Souris SCID , Souris de lignée NOD
8.
Front Immunol ; 15: 1415457, 2024.
Article de Anglais | MEDLINE | ID: mdl-39044825

RÉSUMÉ

Background: The occurrence of peritoneal metastasis (PM) in patients with colorectal cancer (CRC) has a dismal prognosis. There is often limited response to systemic- and immunotherapy, even in microsatellite unstable (MSI) CRC. To overcome therapy resistance, it is critical to understand local immune environment in the peritoneal cavity, and to develop models to study anti-tumor immune responses. Here, we defined the peritoneal immune system (PerIS) in PM-CRC patients and evaluate the pre-clinical potential of a humanized immune system (HIS) mouse model for PM-CRC. Methods: We studied the human PerIS in PM-CRC patients (n=20; MSS 19/20; 95%) and in healthy controls (n=3). HIS mice (NODscid gamma background; n=18) were generated, followed by intraperitoneal injection of either saline (HIS control; n=3) or human MSS/MSI CRC cell lines HUTU80, MDST8 and HCT116 (HIS-PM, n=15). Immune cells in peritoneal fluid and peritoneal tumors were analyzed using cytometry by time of flight (CyTOF). Results: The human and HIS mouse homeostatic PerIS was equally populated by NK cells and CD4+- and CD8+ T cells, however differences were observed in macrophage and B cell abundance. In HIS mice, successful peritoneal engraftment of both MSI and MSS tumors was observed (15/15; 100%). Both in human PM-CRC and in the HIS mouse PM-CRC model, we observed that MSS PM-CRC triggered a CD4+ Treg response in the PerIS, while MSI PM-CRC drives CD8+ TEMs responses. Conclusion: In conclusion, T cell responses in PM-CRC in HIS mice mirror those in human PM-CRC, making this model suitable to study antitumor T cell responses in PM-CRC.


Sujet(s)
Tumeurs colorectales , Modèles animaux de maladie humaine , Tumeurs du péritoine , Animaux , Tumeurs colorectales/immunologie , Tumeurs colorectales/anatomopathologie , Tumeurs du péritoine/secondaire , Tumeurs du péritoine/immunologie , Humains , Souris , Mâle , Femelle , Lignée cellulaire tumorale , Souris de lignée NOD , Souris SCID , Adulte d'âge moyen , Sujet âgé , Microenvironnement tumoral/immunologie , Cellules tueuses naturelles/immunologie
9.
F1000Res ; 13: 484, 2024.
Article de Anglais | MEDLINE | ID: mdl-39036651

RÉSUMÉ

Chemoprophylactic prevention of veterinary heartworm disease in companion animals, caused by the vector-borne nematode parasite Dirofilaria immitis, is a multi-billion-dollar global market. Experimental use of cats and dogs in preclinical heartworm drug testing is increasing due to evolving drug-resistance to frontline macrocyclic lactones and renewed investment in alternative preventative drug research. We and others recently published data demonstrating proof-of-concept of utilising lymphopenic severe-combined immunodeficient (SCID) or Recombination Activating Gene (RAG)2 deficient mice with additional knockout of the IL-2/7 receptor gamma chain (γc) as alternative preventative drug screening research models of dirofilariasis. Here we summarise the current knowledge of candidate immunodeficient mouse models tested, including a comparison of susceptibility using different background strains of mice, different D. immitis isolates, following use of anti-inflammatory treatments to further suppress residual innate immunity, and efficacies achieved against different reference anthelmintics. We supplement this precis with new data on treatment response to the veterinary anthelmintic, oxfendazole, and initial evaluation of D. immitis susceptibility in CB.17 SCID and C57BL/6 RAG2 -/-γc -/- mice. We conclude that in addition to NSG and NXG mice, RAG2 -/-γc -/- mice on either a BALB/c or C57BL/6 background offer an alternative screening model option, widening access to academic and commercial laboratories wishing to pursue initial rapid in vivo drug screening whilst avoiding potentially unnecessary cat or dog testing.


Sujet(s)
Dirofilariose , Modèles animaux de maladie humaine , Souris SCID , Animaux , Chiens , Chats , Souris , Dirofilariose/prévention et contrôle , Dirofilariose/traitement médicamenteux , Dirofilaria immitis/effets des médicaments et des substances chimiques , Dirofilaria immitis/immunologie , Maladies des chats/prévention et contrôle , Maladies des chats/parasitologie , Maladies des chats/traitement médicamenteux , Maladies des chats/immunologie , Maladies des chiens/prévention et contrôle , Maladies des chiens/parasitologie , Maladies des chiens/traitement médicamenteux , Anthelminthiques/usage thérapeutique , Évaluation préclinique de médicament
10.
Life Sci ; 351: 122851, 2024 Aug 15.
Article de Anglais | MEDLINE | ID: mdl-38897345

RÉSUMÉ

AIMS: Pannexin-1 (PANX1) is a hemichannel that releases ATP upon opening, initiating inflammation, cell proliferation, and migration. However, the role of PANX1 channels in colon cancer remains poorly understood, thus constituting the focus of this study. MAIN METHODS: PANX1 mRNA expression was analyzed using multiple cancer databases. PANX1 protein expression and distribution were evaluated by immunohistochemistry on primary tumor tissue and non-tumor colonic mucosa from colon cancer patients. PANX1 inhibitors (probenecid or 10Panx) were used to assess colon cancer cell lines viability. To study the role of PANX1 in vivo, a subcutaneous xenograft model using HCT116 cells was performed in BALB/c NOD/SCID immunodeficient mice to evaluate tumor growth under PANX1 inhibition using probenecid. KEY FINDINGS: PANX1 mRNA was upregulated in colon cancer tissue compared to non-tumor colonic mucosa. Elevated PANX1 mRNA expression in tumors correlated with worse disease-free survival. PANX1 protein abundance was increased on tumor cells compared to epithelial cells in paired samples, in a cancer stage-dependent manner. In vitro and in vivo experiments indicated that blocking PANX1 reduced cell viability and tumor growth. SIGNIFICANCE: PANX1 can be used as a biomarker of colon cancer progression and blocking PANX1 channel opening could be used as a potential therapeutic strategy against this disease.


Sujet(s)
Tumeurs du côlon , Connexines , Évolution de la maladie , Protéines de tissu nerveux , Animaux , Femelle , Humains , Mâle , Souris , Marqueurs biologiques tumoraux/métabolisme , Marqueurs biologiques tumoraux/génétique , Lignée cellulaire tumorale , Prolifération cellulaire , Survie cellulaire , Tumeurs du côlon/anatomopathologie , Tumeurs du côlon/métabolisme , Tumeurs du côlon/génétique , Connexines/métabolisme , Connexines/génétique , Régulation de l'expression des gènes tumoraux , Cellules HCT116 , Souris de lignée BALB C , Souris de lignée NOD , Souris SCID , Protéines de tissu nerveux/métabolisme , Protéines de tissu nerveux/génétique , Probénécide/pharmacologie , Tests d'activité antitumorale sur modèle de xénogreffe
11.
J Exp Clin Cancer Res ; 43(1): 180, 2024 Jun 27.
Article de Anglais | MEDLINE | ID: mdl-38937832

RÉSUMÉ

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by its high metastatic potential, which results in poor patient survival. Cancer-associated fibroblasts (CAFs) are crucial in facilitating TNBC metastasis via induction of mitochondrial biogenesis. However, how to inhibit CAF-conferred mitochondrial biogenesis is still needed to explore. METHODS: We investigated metastasis using wound healing and cell invasion assays, 3D-culture, anoikis detection, and NOD/SCID mice. Mitochondrial biogenesis was detected by MitoTracker green FM staining, quantification of mitochondrial DNA levels, and blue-native polyacrylamide gel electrophoresis. The expression, transcription, and phosphorylation of peroxisome-proliferator activated receptor coactivator 1α (PGC-1α) were detected by western blotting, chromatin immunoprecipitation, dual-luciferase reporter assay, quantitative polymerase chain reaction, immunoprecipitation, and liquid chromatography-tandem mass spectrometry. The prognostic role of PGC-1α in TNBC was evaluated using the Kaplan-Meier plotter database and clinical breast cancer tissue samples. RESULTS: We demonstrated that PGC-1α indicated lymph node metastasis, tumor thrombus formation, and poor survival in TNBC patients, and it was induced by CAFs, which functioned as an inducer of mitochondrial biogenesis and metastasis in TNBC. Shikonin impeded the CAF-induced PGC-1α expression, nuclear localization, and interaction with estrogen-related receptor alpha (ERRα), thereby inhibiting PGC-1α/ERRα-targeted mitochondrial genes. Mechanistically, the downregulation of PGC-1α was mediated by synthase kinase 3ß-induced phosphorylation of PGC-1α at Thr295, which associated with neural precursor cell expressed developmentally downregulated 4e1 recognition and subsequent degradation by ubiquitin proteolysis. Mutation of PGC-1α at Thr295 negated the suppressive effects of shikonin on CAF-stimulated TNBC mitochondrial biogenesis and metastasis in vitro and in vivo. CONCLUSIONS: Our findings indicate that PGC-1α is a viable target for blocking TNBC metastasis by disrupting mitochondrial biogenesis, and that shikonin merits potential for treatment of TNBC metastasis as an inhibitor of mitochondrial biogenesis through targeting PGC-1α.


Sujet(s)
Glycogen synthase kinase 3 beta , Naphtoquinones , Biogenèse des organelles , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes , Tumeurs du sein triple-négatives , Humains , Tumeurs du sein triple-négatives/métabolisme , Tumeurs du sein triple-négatives/anatomopathologie , Tumeurs du sein triple-négatives/traitement médicamenteux , Tumeurs du sein triple-négatives/génétique , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes/métabolisme , Coactivateur 1-alpha du récepteur gamma activé par les proliférateurs de peroxysomes/génétique , Souris , Animaux , Phosphorylation , Glycogen synthase kinase 3 beta/métabolisme , Naphtoquinones/pharmacologie , Naphtoquinones/usage thérapeutique , Femelle , Fibroblastes associés au cancer/métabolisme , Fibroblastes associés au cancer/anatomopathologie , Lignée cellulaire tumorale , Souris SCID , Métastase tumorale , Souris de lignée NOD , Mitochondries/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffe
12.
Int J Mol Sci ; 25(12)2024 Jun 19.
Article de Anglais | MEDLINE | ID: mdl-38928452

RÉSUMÉ

Bone marrow mesenchymal stem cells (BMSCs) are key players in promoting ovarian cancer cell proliferation, orchestrated by the dynamic interplay between cytokines and their interactions with immune cells; however, the intricate crosstalk among BMSCs and cytokines has not yet been elucidated. Here, we aimed to investigate interactions between BMSCs and ovarian cancer cells. We established BMSCs with a characterized morphology, surface marker expression, and tri-lineage differentiation potential. Ovarian cancer cells (SKOV3) cultured with conditioned medium from BMSCs showed increased migration, invasion, and colony formation, indicating the role of the tumor microenvironment in influencing cancer cell behavior. BMSCs promoted SKOV3 tumorigenesis in nonobese diabetic/severe combined immunodeficiency mice, increasing tumor growth. The co-injection of BMSCs increased the phosphorylation of p38 MAPK and GSK-3ß in SKOV3 tumors. Co-culturing SKOV3 cells with BMSCs led to an increase in the expression of cytokines, especially MCP-1 and IL-6. These findings highlight the influence of BMSCs on ovarian cancer cell behavior and the potential involvement of specific cytokines in mediating these effects. Understanding these mechanisms will highlight potential therapeutic avenues that may halt ovarian cancer progression.


Sujet(s)
Prolifération cellulaire , Cytokines , Cellules souches mésenchymateuses , Tumeurs de l'ovaire , Cellules souches mésenchymateuses/métabolisme , Femelle , Tumeurs de l'ovaire/métabolisme , Tumeurs de l'ovaire/anatomopathologie , Humains , Animaux , Cytokines/métabolisme , Souris , Lignée cellulaire tumorale , Techniques de coculture , Microenvironnement tumoral , Mouvement cellulaire , Milieux de culture conditionnés/pharmacologie , Cellules de la moelle osseuse/métabolisme , Souris SCID , Souris de lignée NOD , Différenciation cellulaire
13.
Biomed Pharmacother ; 176: 116887, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38852511

RÉSUMÉ

BACKGROUND: The metastasis of tumors into bone tissue typically leads to intractable pain that is both very disabling and particularly difficult to manage. We investigated here whether riluzole could have beneficial effects for the treatment of prostate cancer-induced bone pain and how it could influence the development of bone metastasis. METHODS: We used a bone pain model induced by intratibial injection of human PC3 prostate cancer cells into male SCID mice treated or not with riluzole administered in drinking water. We also used riluzole in vitro to assess its possible effect on PC3 cell viability and functionality, using patch-clamp. RESULTS: Riluzole had a significant preventive effect on both evoked and spontaneous pain involving the TREK-1 potassium channel. Riluzole did not interfere with PC3-induced bone loss or bone remodeling in vivo. It also significantly decreased PC3 cell viability in vitro. The antiproliferative effect of riluzole is correlated with a TREK-1-dependent membrane hyperpolarization in these cells. CONCLUSION: The present data suggest that riluzole could be very useful to manage evoked and spontaneous hypersensitivity in cancer-induced bone pain and has no significant adverse effect on cancer progression.


Sujet(s)
Analgésiques , Tumeurs osseuses , Douleur cancéreuse , Prolifération cellulaire , Souris SCID , Canaux potassiques à pores à domaines en tandem , Riluzole , Riluzole/pharmacologie , Animaux , Canaux potassiques à pores à domaines en tandem/métabolisme , Mâle , Tumeurs osseuses/traitement médicamenteux , Tumeurs osseuses/métabolisme , Tumeurs osseuses/secondaire , Tumeurs osseuses/anatomopathologie , Tumeurs osseuses/complications , Humains , Douleur cancéreuse/traitement médicamenteux , Douleur cancéreuse/métabolisme , Analgésiques/pharmacologie , Prolifération cellulaire/effets des médicaments et des substances chimiques , Cellules PC-3 , Souris , Survie cellulaire/effets des médicaments et des substances chimiques , Tumeurs de la prostate/traitement médicamenteux , Tumeurs de la prostate/anatomopathologie , Tumeurs de la prostate/métabolisme , Lignée cellulaire tumorale
14.
Front Immunol ; 15: 1362904, 2024.
Article de Anglais | MEDLINE | ID: mdl-38855110

RÉSUMÉ

Introduction: Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies. However, its efficacy in solid tumors is limited by the immunosuppressive tumor microenvironment that compromises CAR T cell antitumor function in clinical settings. To overcome this challenge, researchers have investigated the potential of inhibiting specific immune checkpoint receptors, including A2aR (Adenosine A2 Receptor) and Tim3 (T cell immunoglobulin and mucin domain-containing protein 3), to enhance CAR T cell function. In this study, we evaluated the impact of genetic targeting of Tim3 and A2a receptors on the antitumor function of human mesothelin-specific CAR T cells (MSLN-CAR) in vitro and in vivo. Methods: Second-generation anti-mesothelin CAR T cells were produced using standard cellular and molecular techniques. A2aR-knockdown and/or Tim3- knockdown anti-mesothelin-CAR T cells were generated using shRNA-mediated gene silencing. The antitumor function of CAR T cells was evaluated by measuring cytokine production, proliferation, and cytotoxicity in vitro through coculture with cervical cancer cells (HeLa cell line). To evaluate in vivo antitumor efficacy of manufactured CAR T cells, tumor growth and mouse survival were monitored in a human cervical cancer xenograft model. Results: In vitro experiments demonstrated that knockdown of A2aR alone or in combination with Tim3 significantly improved CAR T cell proliferation, cytokine production, and cytotoxicity in presence of tumor cells in an antigen-specific manner. Furthermore, in the humanized xenograft model, both double knockdown CAR T cells and control CAR T cells could effectively control tumor growth. However, single knockdown CAR T cells were associated with reduced survival in mice. Conclusion: These findings highlight the potential of concomitant genetic targeting of Tim3 and A2a receptors to augment the efficacy of CAR T cell therapy in solid tumors. Nevertheless, caution should be exercised in light of our observation of decreased survival in mice treated with single knockdown MSLN-CAR T cells, emphasizing the need for careful efficacy considerations.


Sujet(s)
Récepteur cellulaire-2 du virus de l'hépatite A , Immunothérapie adoptive , Mésothéline , Récepteurs chimériques pour l'antigène , Tumeurs du col de l'utérus , Tests d'activité antitumorale sur modèle de xénogreffe , Humains , Animaux , Récepteur cellulaire-2 du virus de l'hépatite A/métabolisme , Récepteur cellulaire-2 du virus de l'hépatite A/génétique , Femelle , Tumeurs du col de l'utérus/immunologie , Tumeurs du col de l'utérus/thérapie , Tumeurs du col de l'utérus/génétique , Souris , Immunothérapie adoptive/méthodes , Récepteurs chimériques pour l'antigène/immunologie , Récepteurs chimériques pour l'antigène/génétique , Récepteurs chimériques pour l'antigène/métabolisme , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Lignée cellulaire tumorale , Microenvironnement tumoral/immunologie , Souris SCID
15.
Stem Cell Res Ther ; 15(1): 164, 2024 Jun 09.
Article de Anglais | MEDLINE | ID: mdl-38853275

RÉSUMÉ

BACKGROUND: Transplantation of CD34+ hematopoietic stem and progenitor cells (HSPC) into immunodeficient mice is an established method to generate humanized mice harbouring a human immune system. Different sources and methods for CD34+ isolation have been employed by various research groups, resulting in customized models that are difficult to compare. A more detailed characterization of CD34+ isolates is needed for a better understanding of engraftable hematopoietic and potentially non-hematopoietic cells. Here we have performed a direct comparison of CD34+ isolated from cord blood (CB-CD34+) or fetal liver (FL-CD34+ and FL-CD34+CD14-) and their engraftment into immunocompromised NOD/Shi-scid Il2rgnull (NOG) mice. METHODS: NOG mice were transplanted with either CB-CD34+, FL-CD34+ or FL-CD34+CD14- to generate CB-NOG, FL-NOG and FL-CD14--NOG, respectively. After 15-20 weeks, the mice were sacrificed and human immune cell reconstitution was assessed in blood and several organs. Liver sections were pathologically assessed upon Haematoxylin and Eosin staining. To assess the capability of allogenic tumor rejection in CB- vs. FL-reconstituted mice, animals were subcutaneously engrafted with an HLA-mismatched melanoma cell line. Tumor growth was assessed by calliper measurements and a Luminex-based assay was used to compare the cytokine/chemokine profiles. RESULTS: We show that CB-CD34+ are a uniform population of HSPC that reconstitute NOG mice more rapidly than FL-CD34+ due to faster B cell development. However, upon long-term engraftment, FL-NOG display increased numbers of neutrophils, dendritic cells and macrophages in multiple tissues. In addition to HSPC, FL-CD34+ isolates contain non-hematopoietic CD14+ endothelial cells that enhance the engraftment of the human immune system in FL-NOG mice. We demonstrate that these CD14+CD34+ cells are capable of reconstituting Factor VIII-producing liver sinusoidal endothelial cells (LSEC) in FL-NOG. However, CD14+CD34+ also contribute to hepatic sinusoidal dilatation and immune cell infiltration, which may culminate in a graft-versus-host disease (GVHD) pathology upon long-term engraftment. Finally, using an HLA-A mismatched CDX melanoma model, we show that FL-NOG, but not CB-NOG, can mount a graft-versus-tumor (GVT) response resulting in tumor rejection. CONCLUSION: Our results highlight important phenotypical and functional differences between CB- and FL-NOG and reveal FL-NOG as a potential model to study hepatic sinusoidal dilatation and mechanisms of GVT.


Sujet(s)
Antigènes CD34 , Foie , Animaux , Humains , Antigènes CD34/métabolisme , Souris , Foie/métabolisme , Foie/anatomopathologie , Souris de lignée NOD , Transplantation de cellules souches hématopoïétiques , Souris SCID , Progéniteurs endothéliaux/métabolisme , Progéniteurs endothéliaux/cytologie , Progéniteurs endothéliaux/transplantation , Cellules souches hématopoïétiques/métabolisme , Cellules souches hématopoïétiques/cytologie , Sang foetal/cytologie , Mélanome/anatomopathologie , Mélanome/immunologie
16.
Sci Rep ; 14(1): 13741, 2024 06 14.
Article de Anglais | MEDLINE | ID: mdl-38877072

RÉSUMÉ

Dirofilaria immitis is a mosquito-borne parasitic nematode that causes fatal heartworm disease in canids. The microfilariae are essential for research, including drug screening and mosquito-parasite interactions. However, no reliable methods for maintaining microfilaria long-term are currently available. Therefore, we used severe combined immunodeficiency (SCID) mice to develop a reliable method for maintaining D. immitis microfilaria. SCID mice were injected intravenously with microfilariae isolated from a D. immitis-infected dog. Microfilariae were detected in blood collected from the tail vein 218 days post-inoculation (dpi) and via cardiac puncture 296 dpi. Microfilariae maintained in and extracted from SCID mice showed infectivity and matured into third-stage larvae (L3s) in the vector mosquito Aedes aegypti. L3s can develop into the fourth stage larvae in vitro. Microfilariae from SCID mice respond normally to ivermectin in vitro. The microfilariae in SCID mice displayed periodicity in the peripheral circulation. The SCID mouse model aided in the separation of microfilariae from cryopreserved specimens. The use of SCID mice enabled the isolation and sustained cultivation of microfilariae from clinical samples. These findings highlight the usefulness of the SCID mouse model for studying D. immitis microfilaremia in canine heartworm research.


Sujet(s)
Dirofilaria immitis , Dirofilariose , Modèles animaux de maladie humaine , Souris SCID , Microfilaria , Animaux , Chiens , Dirofilariose/parasitologie , Souris , Maladies des chiens/parasitologie , Aedes/parasitologie , Larve , Ivermectine/usage thérapeutique
17.
J Exp Clin Cancer Res ; 43(1): 163, 2024 Jun 11.
Article de Anglais | MEDLINE | ID: mdl-38863037

RÉSUMÉ

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment. METHODS: Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC50 of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays. RESULTS: BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t1/2, ~8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade. CONCLUSIONS: BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.


Sujet(s)
Réparation de l'ADN par jonction d'extrémités , Protein-Serine-Threonine Kinases , Radiotolérance , Tumeurs du sein triple-négatives , Humains , Tumeurs du sein triple-négatives/radiothérapie , Tumeurs du sein triple-négatives/métabolisme , Tumeurs du sein triple-négatives/génétique , Tumeurs du sein triple-négatives/anatomopathologie , Animaux , Femelle , Souris , Lignée cellulaire tumorale , Protein-Serine-Threonine Kinases/métabolisme , Protein-Serine-Threonine Kinases/génétique , Tests d'activité antitumorale sur modèle de xénogreffe , Prolifération cellulaire , Régulation de l'expression des gènes tumoraux , Souris SCID
18.
Phytomedicine ; 130: 155537, 2024 Jul 25.
Article de Anglais | MEDLINE | ID: mdl-38823344

RÉSUMÉ

BACKGROUND: Aberrant activation of autophagy in triple-negative breast cancer (TNBC) has led researchers to investigate potential therapeutic strategies targeting this process. The regulation of autophagy is significantly influenced by METTL3. Our previous research has shown that the Panax ginseng-derived compound, 20(R)-panaxatriol (PT), has potential as an anti-tumor agent. However, it remains unclear whether PT can modulate autophagy through METTL3 to exert its anti-tumor effects. OBJECTIVE: Our objective is to investigate whether PT can regulate autophagy in TNBC cells and elucidate the molecular mechanisms. STUDY DESIGN: For in vitro experiments, we employed SUM-159-PT and MDA-MB-231 cells. While in vivo experiments involved BALB/c nude mice and NOD/SCID mice. METHODS: In vitro, TNBC cells were treated with PT, and cell lines with varying expression levels of METTL3 were established. We assessed the impact on tumor cell activity and autophagy by analyzing autophagic flux, Western Blot (WB), and methylation levels. In vivo, subcutaneous transplantation models were established in BALB/c nude and NOD/SCID mice to observe the effect of PT on TNBC growth. HE staining and immunofluorescence were employed to analyze histopathological changes in tumor tissues. MeRIP-seq and dual-luciferase reporter gene assays were used to identify key downstream targets. Additionally, the silencing of STIP1 Homology And U-Box Containing Protein 1 (STUB1) explored PT's effects. The mechanism of PT's action on STUB1 via METTL3 was elucidated through mRNA stability assays, mRNA alternative splicing analysis, and nuclear-cytoplasmic mRNA separation. RESULTS: In both in vivo and in vitro experiments, it was discovered that PT significantly upregulates the expression of METTL3, leading to autophagy inhibition and therapeutic effects in TNBC. Simultaneously, through MeRIP-seq analysis and dual-luciferase reporter gene assays, we have demonstrated that PT modulates STUB1 via METTL3, influencing autophagy in TNBC cells. Furthermore, intriguingly, PT extends the half-life of STUB1 mRNA by enhancing its methylation modification, thereby enhancing its stability. CONCLUSION: In summary, our research reveals that PT increases STUB1 m6A modification through a METTL3-mediated mechanism in TNBC cells, inhibiting autophagy and further accentuating its anti-tumor properties. Our study provides novel mechanistic insights into TNBC pathogenesis and potential drug targets for TNBC.


Sujet(s)
Autophagie , Methyltransferases , Souris de lignée BALB C , Souris nude , Tumeurs du sein triple-négatives , Ubiquitin-protein ligases , Animaux , Tumeurs du sein triple-négatives/traitement médicamenteux , Humains , Autophagie/effets des médicaments et des substances chimiques , Femelle , Lignée cellulaire tumorale , Methyltransferases/métabolisme , Ubiquitin-protein ligases/métabolisme , Souris SCID , Souris de lignée NOD , Souris , Antinéoplasiques d'origine végétale/pharmacologie , Tests d'activité antitumorale sur modèle de xénogreffe , Panax/composition chimique , Adénosine/analogues et dérivés , Adénosine/pharmacologie
19.
J Exp Clin Cancer Res ; 43(1): 161, 2024 Jun 11.
Article de Anglais | MEDLINE | ID: mdl-38858661

RÉSUMÉ

BACKGROUND: Cancer-associated fibroblasts (CAFs) play a significant role in fueling prostate cancer (PCa) progression by interacting with tumor cells. A previous gene expression analysis revealed that CAFs up-regulate genes coding for voltage-gated cation channels, as compared to normal prostate fibroblasts (NPFs). In this study, we explored the impact of antiarrhythmic drugs, known cation channel inhibitors, on the activated state of CAFs and their interaction with PCa cells. METHODS: The effect of antiarrhythmic treatment on CAF activated phenotype was assessed in terms of cell morphology and fibroblast activation markers. CAF contractility and migration were evaluated by 3D gel collagen contraction and scratch assays, respectively. The ability of antiarrhythmics to impair CAF-PCa cell interplay was investigated in CAF-PCa cell co-cultures by assessing tumor cell growth and expression of epithelial-to-mesenchymal transition (EMT) markers. The effect on in vivo tumor growth was assessed by subcutaneously injecting PCa cells in SCID mice and intratumorally administering the medium of antiarrhythmic-treated CAFs or in co-injection experiments, where antiarrhythmic-treated CAFs were co-injected with PCa cells. RESULTS: Activated fibroblasts show increased membrane conductance for potassium, sodium and calcium, consistently with the mRNA and protein content analysis. Antiarrhythmics modulate the expression of fibroblast activation markers. Although to a variable extent, these drugs also reduce CAF motility and hinder their ability to remodel the extracellular matrix, for example by reducing MMP-2 release. Furthermore, conditioned medium and co-culture experiments showed that antiarrhythmics can, at least in part, reverse the protumor effects exerted by CAFs on PCa cell growth and plasticity, both in androgen-sensitive and castration-resistant cell lines. Consistently, the transcriptome of antiarrhythmic-treated CAFs resembles that of tumor-suppressive NPFs. In vivo experiments confirmed that the conditioned medium or the direct coinjection of antiarrhythmic-treated CAFs reduced the tumor growth rate of PCa xenografts. CONCLUSIONS: Collectively, such data suggest a new therapeutic strategy for PCa based on the repositioning of antiarrhythmic drugs with the aim of normalizing CAF phenotype and creating a less permissive tumor microenvironment.


Sujet(s)
Antiarythmiques , Fibroblastes associés au cancer , Tumeurs de la prostate , Mâle , Humains , Tumeurs de la prostate/traitement médicamenteux , Tumeurs de la prostate/métabolisme , Tumeurs de la prostate/anatomopathologie , Tumeurs de la prostate/génétique , Antiarythmiques/pharmacologie , Antiarythmiques/usage thérapeutique , Souris , Animaux , Fibroblastes associés au cancer/métabolisme , Fibroblastes associés au cancer/effets des médicaments et des substances chimiques , Phénotype , Lignée cellulaire tumorale , Repositionnement des médicaments , Souris SCID , Tests d'activité antitumorale sur modèle de xénogreffe , Transition épithélio-mésenchymateuse/effets des médicaments et des substances chimiques , Mouvement cellulaire/effets des médicaments et des substances chimiques
20.
Nat Commun ; 15(1): 4841, 2024 Jun 06.
Article de Anglais | MEDLINE | ID: mdl-38844783

RÉSUMÉ

Kaposi sarcoma associated herpesvirus (KSHV) is associated with around 1% of all human tumors, including the B cell malignancy primary effusion lymphoma (PEL), in which co-infection with the Epstein Barr virus (EBV) can almost always be found in malignant cells. Here, we demonstrate that KSHV/EBV co-infection of mice with reconstituted human immune systems (humanized mice) leads to IgM responses against both latent and lytic KSHV antigens, and expansion of central and effector memory CD4+ and CD8+ T cells. Among these, KSHV/EBV dual-infection allows for the priming of CD8+ T cells that are specific for the lytic KSHV antigen K6 and able to kill KSHV/EBV infected B cells. This suggests that K6 may represent a vaccine antigen for the control of KSHV and its associated pathologies in high seroprevalence regions, such as Sub-Saharan Africa.


Sujet(s)
Lymphocytes B , Lymphocytes T CD8+ , Herpèsvirus humain de type 8 , Animaux , Herpèsvirus humain de type 8/immunologie , Humains , Lymphocytes B/immunologie , Souris , Lymphocytes T CD8+/immunologie , Infections à virus Epstein-Barr/immunologie , Infections à virus Epstein-Barr/virologie , Co-infection/immunologie , Co-infection/virologie , Lymphocytes T CD4+/immunologie , Herpèsvirus humain de type 4/immunologie , Infections à Herpesviridae/immunologie , Infections à Herpesviridae/virologie , Immunoglobuline M/immunologie , Antigènes viraux/immunologie , Souris SCID , Lymphome primitif des séreuses/immunologie , Lymphome primitif des séreuses/virologie , Anticorps antiviraux/immunologie
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